The aims of the program are to identify mechanisms underlying normal mammalian differentiation, in relation to gene controls; and to understand the developmental basis for malignancy and for genetic diseases, ---particularly those diseases analogous to human diseases. These goals are being largely pursued through various experimental uses of genetically mosaic (allophenic) mice. In these animals, the two cell populations co-existing throughout development and postnatal life are from a normal and a genetically defective strain; from a normal strain and a strain susceptible to a particular malignancy; or from a normal strain and actually malignant teratocarcinoma stem cells. The teratocarcinoma cells become completely normalized when they are placed in a normal early embryo environment. Normal germ cells may also be derived from the tumor, and give rise to progeny. Therefore, experiments are being undertaken in which the tumor cells are first being mutagenized and subjected to selection in vitro for specific genetic lesions; they are then introduced into normal blastocysts. This will enable production of animals in which the effects of a biochemically identified lesion on differentiation may be analyzed in vivo. These new experiments are designed to provide laboratory animal models of a wide range of human genetic diseases; and to increase our understanding of genetic control of mammalian differentiation. Efforts are also in progress to reverse other malignancies by introducing the stem cells into normal embryos. BIBLIOGRAPHIC REFERENCES: Illmensee, K., and Mintz, B. (1976). Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc. Nat. Acad. Sci. U.S. 73, 549-553. Dewey, M.J., Gervais, A.G., and Mintz, G. (1976). Brain and ganglion development from two genotypic classes of cells in allophenic mice. Develop. Biol. 50, 68-81.